Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury.

TitleSphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury.
Publication TypeJournal Article
Year of Publication2013
AuthorsNatarajan V, Dudek SM, Jacobson JR, Moreno-Vinasco L, Huang LShuang, Abassi T, Mathew B, Zhao Y, Wang L, Bittman R, Weichselbaum R, Berdyshev E, Garcia JGN
JournalAm J Respir Cell Mol Biol
Volume49
Issue1
Pagination6-17
Date Published2013 Jul
ISSN Number1535-4989
KeywordsAcute Lung Injury, Animals, Anti-Inflammatory Agents, Biomarkers, Capillary Permeability, Fingolimod Hydrochloride, Humans, Lung, Lysophospholipids, Membrane Proteins, Nerve Tissue Proteins, Phosphotransferases (Alcohol Group Acceptor), Pneumonia, Propylene Glycols, Receptors, Lysosphingolipid, Sepsis, Sphingosine, Transferases (Other Substituted Phosphate Groups), Translational Medical Research
Abstract

<p>Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.</p>

DOI10.1165/rcmb.2012-0411TR
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID23449739
PubMed Central IDPMC3727889
Grant ListP01 HL058064 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
PPG HL58064 / HL / NHLBI NIH HHS / United States
PPG HL98050 / HL / NHLBI NIH HHS / United States